Schistosome Soluble Egg Antigen Decreases Mycobacterium tuberculosis-Specific CD4+ T-Cell Effector Function With Concomitant Arrest of Macrophage Phago-Lysosome Maturation.
Helminth-infected individuals possess a higher risk of developing tuberculosis, but the precise immunologic mechanism of Mycobacterium tuberculosis control remains unclear. We hypothesized that a perturbation of the M. tuberculosis-specific CD4(+) T-cell response weakens the ability of macrophages to contain M. tuberculosis We exposed peripheral blood mononuclear cells from M. tuberculosis-infected humans to schistosome soluble egg antigen (SEA) and then profiled M. tuberculosis-specific CD4(+) T cells via multiparametric flow cytometry. SEA decreased the frequency of cells producing interferon γ (6.79% vs 3.20%; P = .017) and tumor necrosis factor α (6.98% vs 2.96%; P = .012), with a concomitant increase in the median fluorescence intensity of interleukin 4 (IL-4; P < .05) and interleukin 10 (IL-10; 1440 vs 1273; P < .05). Macrophages polarized with SEA-exposed, autologous CD4(+) T-cell supernatant had a 2.19-fold decreased colocalization of lysosomes and M. tuberculosis (P < .05). When polarized with IL-4 or IL-10, macrophages had increased expression of CD206 (P < .0001), 1.5-fold and 1.9 fold increased intracellular numbers of M. tuberculosis per macrophage (P < .0005), and 1.4-fold and 1.7-fold decreased colocalization between M. tuberculosis and lysosomes (P < .001). This clarifies a relationship in which helminth-induced CD4(+) T cells disrupt M. tuberculosis control by macrophages, thereby providing a mechanism for the observation that helminth infection advances the progression of tuberculosis among patients with M. tuberculosis infection.


Characterization of urinary metabolites from Sprague-Dawley rats and B6C3F1 mice exposed to [1,2,3,4-13C]butadiene.
1,3-Butadiene (BD) is used in the production of synthetic rubber and other resins. Carcinogenic effects have been observed in laboratory animals exposed to BD, with mice being more sensitive than rats. Metabolic oxidation of butadiene to epoxides is believed to be a crucial step in the initiation of tumors by BD. However, limited information is available that describes the in vivo metabolism of BD. Male Sprague-Dawley rats and B6C3F1 mice were exposed to 800 ppm [1,2 3,4-13C]butadiene for 5 h, and urine was collected during and for 20 h following exposure. Urinary metabolites were characterized using 1- and 2-dimensional methods of NMR spectroscopy. Three metabolites previously detected in vivo, N-acetyl-S-(2-hydroxy-3-butenyl)-L-cysteine, N-acetyl-S-(1-(hydroxymethyl)-2-propenyl)-L-cysteine, and N-acetyl-S-(3,4-dihydroxybutyl)-L-cysteine, were present in both rat and mouse urine, accounting for 87% and 73% of the total metabolites excreted, respectively. A fourth metabolite, previously detected in vitro, 3-butene-1,2-diol, was also present in both rat and mouse urine and comprised 5% and 3% of the total metabolites excreted, respectively. An additional metabolite detected only in mouse urine that is derived from glutathione conjugation with epoxybutene was identified as S-(1-(hydroxymethyl)-2-propenyl)-L-cysteine (4%). N-Acetyl-S-(1-hydroxy-3-butenyl)-L-cysteine (4%), detected in mouse urine, is a thiohemiacetal product of 3-butenal. Additionally, mice excreted N-acetyl-S-(3-hydroxypropyl)-L-cysteine (5%) and N-acetyl-S-(2-carboxyethyl)-L-cysteine (5%), which could be derived from further metabolism of N-acetyl-S-(3,4-dihydroxybutyl)-L-cysteine or from glutathione conjugation with acrolein. Mice excreted N-acetyl-S-(1-(hydroxymethyl)-3,4-dihydroxypropyl)-L-cysteine (5%), which could be derived from glutathione conjugation with diepoxybutane (BDE), while rats excreted 1,3-dihydroxypropanone (5%), which may be derived from hydrolysis of BDE. These studies indicate that reactive aldehydes are produced as metabolites of BD in vivo, in addition to the reactive monoepoxide and diepoxide of BD. The greater toxicity of BD in mice compared with rats may be attributed to the greater ability of rats to detoxify BDE via hydrolysis, and/or to the production of reactive aldehydes.


Identification of cell signaling molecules by expression cloning.
Using expression cloning one can isolate proteins with specific biological functions. This methodology can be adapted for the identification of novel players in the regulation of cell signaling. Here, we describe an expression cloning strategy to identify suppressors of Ras signaling. This screen is based on the observation that the activation of the small guanosine triphosphate (GTP)-binding protein H-Ras initiates a mitogen-activated protein kinase (MAPK)-dependent signaling pathway that inactivates integrin ligand binding. Our strategy depends on flow cytometry and a monoclonal antibody that recognizes integrin activation states. Flow cytometry enhances the screen's sensitivity thereby allowing us to examine function quantitatively at the level of a single cell millions of times in one screen. The following protocol provides a detailed method for the isolation of proteins that regulate cell signaling.


Water-displacement plethysmography: a technique for the simultaneous thermal manipulation and measurement of whole-hand and whole-foot blood flows.
The purpose of this project was to design, construct and validate water-displacement plethysmographs for the forearm, hand and foot that could clamp segmental skin temperature whilst simultaneously measuring cutaneous blood flow. Two experiments were performed. In the first, the forearm plethysmograph was validated against a mercury-in-silastic plethysmograph under thermoneutral conditions, with and without forearm heating. Cutaneous vascular conductance was elevated almost three-fold by this treatment, however, there were no significant differences between the two forms of plethysmography in either state (P > 0.05). In study two, hand and foot blood flows were measured under clamped thermoneutral conditions, but with three local skin temperature treatments (5, 25, 40 °C). The hand had significantly higher blood flows than the foot at both 25 °C (4.07 versus 2.20 mL.100 mL( - 1).min( - 1); P < 0.05) and 40 °C (8.20 versus 4.47 mL.100 mL( - 1).min( - 1); P < 0.05). The foot was maximally constricted during the two lower temperatures, yet the cutaneous thermal sensitivity of the hand was almost two-fold greater (P < 0.05). This evidence supports the significant role played by these appendages in heat loss and conservation, and these plethysmographs will now be used to map cutaneous vascular responses (forearm, hand, calf, foot) across combinations of core and local skin temperatures.


Lack of posterior occlusal support predicts the reduction in walking speed in 80-year-old Japanese adults: A 3-year prospective cohort study with propensity score analysis by the SONIC Study Group.
To investigate the association between posterior occlusal support by residual teeth and the reduction in walking speed in 80-year-old Japanese adults using propensity score matching. Previous studies have demonstrated an association between oral status and motor function; however, most of these studies had a cross-sectional design. This study included 353 community-dwelling Japanese people aged 79-81 years. Low walking speed was defined as ≤0.8 m/s, and participants with a low walking speed at baseline were excluded. The participants were divided into two groups: with or without posterior occlusal support by residual teeth at baseline. Propensity score matching was used to reduce the effects of bias by matching participants with and without posterior occlusal support according to similar background factors at baseline. Conditional logistic regression was conducted to determine low walking speed at the 3-year follow-up, which included posterior occlusal support as an independent variable with matching data. Before matching for posterior occlusal support, significant differences existed between the groups in terms of sex, years of education, height, weight and grip strength. However, after matching, there was no significant difference between the groups in any characteristic. Logistic regression analysis showed that posterior occlusal support is a significant variable (odds ratio = 1.88; P = 0.04) associated with reduced walking speed. Lack of posterior occlusal support at baseline independently predicted the incidence of reduced walking speed over 3 years.


Evaluation of a peer network-based sexual risk reduction intervention for men in beer halls in Zimbabwe: results from a randomized controlled trial.
While much emphasis has been placed on involving men in AIDS prevention in sub-Saharan Africa, there remain few rigorously evaluated interventions in this area. A particularly appealing point of intervention is the sexual risk behavior associated with men's alcohol consumption. This article reports the outcomes of The Sahwira HIV Prevention Program, a male-focused, peer-based intervention promoting the idea that men can assist their friends in avoiding high-risk sexual encounters associated with alcohol drinking. The intervention was evaluated in a randomized, controlled trial (RCT) implemented in 24 beer halls in Harare, Zimbabwe. A cadre of 413 male beer hall patrons (~20% of the patronage) was trained to assist their male peers within their friendship networks. Activities included one-on-one interactions, small group discussions, and educational events centering on the theme of men helping their male friends avoid risk. Venues were randomized into 12 control versus 12 intervention beer halls with little cross-contamination between study arms. The penetration and impact of the intervention were assessed by pre- and post-intervention cross-sectional surveys of the beer hall patronage. The intervention was implemented with a high degree of fidelity to the protocol, with exposure to the intervention activities significantly higher among intervention patrons compared to control. While we found generally declining levels of risk behavior in both study arms from baseline to post-intervention, we found no evidence of an impact of the intervention on our primary outcome measure: episodes of unprotected sex with non-wife partners in the preceding 6 months (median 5.4 episodes for men at intervention beer halls vs. 5.1 among controls, P = 0.98). There was also no evidence that the intervention reduced other risks for HIV. It remains an imperative to find ways to productively engage men in AIDS prevention, especially in those venues where male bonding, alcohol consumption, and sexual risk behavior are intertwined.


Protein tyrosine kinase 6 promotes ERBB2-induced mammary gland tumorigenesis in the mouse.
Protein tyrosine kinase 6 (PTK6) expression, activation, and amplification of the PTK6 gene have been reported in ERBB2/HER2-positive mammary gland cancers. To explore contributions of PTK6 to mammary gland tumorigenesis promoted by activated ERBB2, we crossed Ptk6-/- mice with the mouse mammary tumor virus-ERBB2 transgenic mouse line expressing activated ERBB2 and characterized tumor development and progression. ERBB2-induced tumorigenesis was significantly delayed and diminished in mice lacking PTK6. PTK6 expression was induced in the mammary glands of ERBB2 transgenic mice before tumor development and correlated with activation of signal transducer and activator of transcription 3 (STAT3) and increased proliferation. Disruption of PTK6 impaired STAT3 activation and proliferation. Phosphorylation of the PTK6 substrates focal adhesion kinase (FAK) and breast cancer anti-estrogen resistance 1 (BCAR1; p130CAS) was decreased in Ptk6-/- mammary gland tumors. Reduced numbers of metastases were detected in the lungs of Ptk6-/- mice expressing activated ERBB2, compared with wild-type ERBB2 transgenic mice. PTK6 activation was detected at the edges of ERBB2-positive tumors. These data support roles for PTK6 in both ERBB2-induced mammary gland tumor initiation and metastasis, and identify STAT3, FAK, and BCAR1 as physiologically relevant PTK6 substrates in breast cancer. Including PTK6 inhibitors as part of a treatment regimen could have distinct benefits in ERBB2/HER2-positive breast cancers.


The burden of parasitic zoonoses in Nepal: a systematic review.
Parasitic zoonoses (PZs) pose a significant but often neglected threat to public health, especially in developing countries. In order to obtain a better understanding of their health impact, summary measures of population health may be calculated, such as the Disability-Adjusted Life Year (DALY). However, the data required to calculate such measures are often not readily available for these diseases, which may lead to a vicious circle of under-recognition and under-funding. We examined the burden of PZs in Nepal through a systematic review of online and offline data sources. PZs were classified qualitatively according to endemicity, and where possible a quantitative burden assessment was conducted in terms of the annual number of incident cases, deaths and DALYs. Between 2000 and 2012, the highest annual burden was imposed by neurocysticercosis and congenital toxoplasmosis (14,268 DALYs [95% Credibility Interval (CrI): 5450-27,694] and 9255 DALYs [95% CrI: 6135-13,292], respectively), followed by cystic echinococcosis (251 DALYs [95% CrI: 105-458]). Nepal is probably endemic for trichinellosis, toxocarosis, diphyllobothriosis, foodborne trematodosis, taeniosis, and zoonotic intestinal helminthic and protozoal infections, but insufficient data were available to quantify their health impact. Sporadic cases of alveolar echinococcosis, angiostrongylosis, capillariosis, dirofilariosis, gnathostomosis, sparganosis and cutaneous leishmaniosis may occur. In settings with limited surveillance capacity, it is possible to quantify the health impact of PZs and other neglected diseases, thereby interrupting the vicious circle of neglect. In Nepal, we found that several PZs are endemic and are imposing a significant burden to public health, higher than that of malaria, and comparable to that of HIV/AIDS. However, several critical data gaps remain. Enhanced surveillance for the endemic PZs identified in this study would enable additional burden estimates, and a more complete picture of the impact of these diseases.


"It's for us -newcomers, LGBTQ persons, and HIV-positive persons. You feel free to be": a qualitative study exploring social support group participation among African and Caribbean lesbian, gay, bisexual and transgender newcomers and refugees in Toronto, Canada.
Stigma and discrimination harm the wellbeing of lesbian, gay, bisexual and transgender (LGBT) people and contribute to migration from contexts of sexual persecution and criminalization. Yet LGBT newcomers and refugees often face marginalization and struggles meeting the social determinants of health (SDOH) following immigration to countries such as Canada. Social isolation is a key social determinant of health that may play a significant role in shaping health disparities among LGBT newcomers and refugees. Social support may moderate the effect of stressors on mental health, reduce social isolation, and build social networks. Scant research, however, has examined social support groups targeting LGBT newcomers and refugees. The purpose of this qualitative study was to explore experiences of social support group participation among LGBT African and Caribbean newcomers and refugees in an urban Canadian city. We conducted 3 focus groups with a venue-based sample of LGBT African and Caribbean newcomers and refugees (n = 29) who attended social support groups at an ethno-specific AIDS Service Organization. Focus groups followed a semi-structured interview guide and were analyzed using narrative thematic techniques. Participant narratives highlighted immigration stressors, social isolation, mental health issues, and challenges meeting the SDOH. Findings reveal multi-level benefits of social support group participation at intrapersonal (self-acceptance, improved mental health), interpersonal (reduced isolation, friendships), community (reciprocity, reduced stigma and discrimination), and structural (housing, employment, immigration, health care) levels. Findings suggest that social support groups tailored for LGBT African and Caribbean newcomers and refugees can address social isolation, community resilience, and enhance resource access. Health care providers can provide support groups, culturally and LGBT competent health services, and resource access to promote LGBT newcomers and refugees' health and wellbeing.


Cyclohexa-1,3-diene-based dihydrogen and hydrosilane surrogates in B(C6F5)3-catalysed transfer processes.
The cyclohexa-1,3-diene motif is introduced as an equally effective alternative to the cyclohexa-1,4-diene platform in B(C6F5)3-catalysed transfer processes. The transfer hydrogenation of alkenes is realised with α-terpinene and the related transfer hydrosilylation is achieved with 5-trimethylsilyl-substituted cyclohexa-1,3-diene. Both yields and substrate scope are comparable with the prior systems.


Subacute inhalation toxicity study of synthetic amorphous silica nanoparticles in Sprague-Dawley rats.
Synthetic amorphous silica nanoparticles (SiNPs) are one of the most applied nanomaterials and are widely used in a broad variety of industrial and biomedical fields. However, no recent long-term inhalation studies evaluating the toxicity of SiNPs are available and results of acute studies are limited. Thus, we conducted a subacute inhalation toxicity study of SiNPs in Sprague-Dawley rats using a nose-only inhalation system. Rats were separated into four groups and target concentrations selected in this study were as follows: control (fresh air), low- (0.407 ± 0.066 mg/m3), middle- (1.439 ± 0.177 mg/m3) and high-concentration group (5.386 ± 0.729 mg/m3), respectively. The rats were exposed to SiNPs for four consecutive weeks (6 hr/day, 5 days/week) except for control group of rats which received filtered fresh air. After 28-days of inhalation exposure to SiNPs, rats were sacrificed after recovery periods of one, seven and 28 days. Although there were minimal toxic changes such as temporary decrease of body weight after exposure, increased levels of red blood cells (RBCs) and hemoglobin (Hb) concentration, the lung histopathological findings and inflammatory markers in bronchoalveolar lavage (BAL) fluid including polymorphonuclear (PMN) leukocyte, lactate dehydrogenase (LDH), albumin and protein did not show significant changes at any recovery period. The results of this study suggest that the subacute inhalation of SiNPs had no toxic effects on the lung of rats at the concentrations and selected time points used in this study.


Systemic antibiotic treatment of clinical endometritis in dairy cows with ceftiofur or two doses of cloprostenol in a 14-d interval.
The objective of the study was to compare the systemic antibiotic treatment of clinical endometritis in dairy cows with ceftiofur with a treatment protocol consisting of two doses of prostaglandin F(2alpha) analogue cloprostenol in a 14-d interval. On 2 commercial dairy farms, housing a total of 1900 Holstein cows, all cows that calved between June 2008 and January 2009 were examined 21-27d in milk (DIM) by vaginoscopy. Cows with clinical signs of endometritis, i.e. vaginal discharge containing flecks of pus, mucopurulent material or purulent mucus, were randomly allocated to one of two treatment groups. Cows in group CEF (n=141) received 1 mg/kg BW of ceftiofur (i.m.) on 3 consecutive days. Cows in group CLP (n=140) received 0.5 mg of cloprostenol (i.m.) at the day of enrolment and 14d later. All cows were re-examined by vaginoscopy 42-48 DIM. Proportion of cows cured, i.e. cows with clear, translucent or no mucus, 42-48 DIM (74.2 and 80.2% in groups CEF and CLP, respectively) was not affected by treatment group (P=0.09). The voluntary waiting period was set at 40 DIM. Artificial insemination (AI) submission rate, days to first service, first service conception rate, days open and proportion of cows pregnant did not differ between the groups. In conclusion, the systemic treatment with 1.0 mg/kg BW of ceftiofur on 3 consecutive days in cows with signs of clinical endometritis 21-27 DIM was equivalent to an intervention protocol consisting of two doses of cloprostenol in a 14-d interval.


Cancer mortality among women frequently exposed to radiographic examinations for spinal disorders.
We studied cancer mortality in a cohort of 5,573 women with scoliosis and other spine disorders who were diagnosed between 1912 and 1965 and were exposed to frequent diagnostic X-ray procedures. Patients were identified from medical records in 14 orthopedic medical centers in the United States and followed for vital status and address through December 31, 2004, using publicly available regional, state and nationwide databases. Causes of death were obtained from death certificates or through linkage with the National Death Index (NDI). Statistical analyses included standardized mortality ratios (SMR = observed/expected) based on death rates for U.S. females and internal comparisons using Cox regression models with attained age as the time scale. Diagnostic radiation exposure was estimated from radiology files for over 137,000 procedures; estimated average cumulative radiation doses to the breast, lung, thyroid and bone marrow were 10.9, 4.1, 7.4 and 1.0 cGy, respectively. After a median follow-up period of 47 years, 1527 women died, including 355 from cancer. Cancer mortality was 8% higher than expected (95% CI = 0.97-1.20). Mortality from breast cancer was significantly elevated (SMR = 1.68; 95% CI: 1.38-2.02), whereas death rates from several other cancers were below expectation, in particular lung (SMR = 0.77), cervical (SMR = 0.31), and liver (SMR = 0.17). The excess relative risk (ERR) for breast cancer mortality increased significantly with 10-year lagged radiation dose to the breast (ERR/Gy = 3.9; 95% CI: 1.0-9.3).


The Eurasian heartland: a continental perspective on Y-chromosome diversity.
The nonrecombining portion of the human Y chromosome has proven to be a valuable tool for the study of population history. The maintenance of extended haplotypes characteristic of particular geographic regions, despite extensive admixture, allows complex demographic events to be deconstructed. In this study we report the frequencies of 23 Y-chromosome biallelic polymorphism haplotypes in 1,935 men from 49 Eurasian populations, with a particular focus on Central Asia. These haplotypes reveal traces of historical migrations, and provide an insight into the earliest patterns of settlement of anatomically modern humans on the Eurasian continent. Central Asia is revealed to be an important reservoir of genetic diversity, and the source of at least three major waves of migration leading into Europe, the Americas, and India. The genetic results are interpreted in the context of Eurasian linguistic patterns.


The function of the acromioclavicular and coracoclavicular ligaments in shoulder motion: a whole-cadaver study.
Scapulothoracic dyskinesis is an important consequence of acromioclavicular joint dislocations. However, no reports have described changes in 3-dimensional motions of the scapula and clavicle with respect to the thorax caused by acromioclavicular joint dislocation. Sectioning of the acromioclavicular (AC) and coracoclavicular (CC) ligaments affects scapular and clavicular motion in a whole-cadaver model. Controlled laboratory study. We evaluated shoulder girdle motion (scapula, clavicle, and humerus) relative to the thorax of 14 shoulders from 8 whole cadavers after sequential sectioning of the AC and CC ligaments (trapezoid and conoid ligaments). An electromagnetic tracking device measured 3-dimensional kinematics of the scapula and clavicle during humerothoracic elevation in the coronal and sagittal planes and adduction in the horizontal plane. Sectioning of the AC ligament increased clavicular retraction during sagittal plane elevation and horizontal plane adduction. Sectioning of the trapezoid ligament decreased scapular external rotation during sagittal plane elevation and horizontal plane adduction. Sectioning of the conoid ligament decreased scapular posterior tilting during sagittal plane elevation and horizontal plane adduction. Acromioclavicular and CC ligament sectioning also delayed clavicular posterior rotation and increased clavicular upward rotation during coronal plane elevation. Our study revealed that AC and CC ligament disruption affected in vitro shoulder girdle kinematics in the whole-cadaver model. The results of this cadaveric study revealed that AC and CC ligament disruption could cause dyskinesis of the scapula and clavicle. The kinematic changes could be a potential source of pain and dysfunction in the shoulder with AC joint dislocation, and therefore surgical reconstruction may be indicated in certain patients.


Long-term survival in patients with acute leukemia and chronic disseminated candidiasis despite minimal antileukemic therapy.
Infections may require discontinuation of antineoplastic chemotherapy, which, in turn, renders patients vulnerable to disease progression or relapse. We identified six patients with acute leukemia in whom antineoplastic treatment had to be discontinued because of chronic disseminated candidiasis (CDC). However, despite minimal antileukemic treatment, all patients remained in complete remission. Immunologic mechanisms associated with CDC might have had an antileukemic effect.


Effect of high-fat mixed lipid diet and swimming on fibre types in skeletal muscles of rats with colon tumours.
Skeletal muscle fibre types, whose characteristics are determined by myosin heavy chain (MyHC) isoforms, can adapt to changed physiological demands with changed MyHC isoform expression resulting in the fibre type transitions. The endurance training is known to induce fast-to-slow transitions and has beneficial effect in carcinogenesis, whereas the effect of an excessive fat intake and its interaction with the effect of swimming are less conclusive. Therefore, we studied the effect of high-fat mixed lipid (HFML) diet and long-term (21-week) swimming on fibre type transitions and their average diameters by immunohistochemical demonstration of MyHC isoforms in slow soleus (SOL), fast extensor digitorum longus (EDL), and mixed gastrocnemius medialis and lateralis (GM, GL) muscles, divided to deep and superficial portions (GMd, GMs, GLd, GLs), of sedentary and swimming Wistar rats with experimentally (dimethylhydrazine) induced colon tumours and fed either with HFML or low-fat corn oil (LFCO) diet. HFML diet induced only a trend for fast-to-slow transitions in SOL and in the opposite direction in GMd. Swimming triggered significant transitions in unexpected slow-to-fast direction in SOL, whereas in GMs the transitions had tendency to proceed in the expected fast-to-slow direction. The average diameters of fibre types were mostly unaffected. Hence, it can be concluded that if present, the effects of HFML diet and swimming on fibre type transitions were counteractive and muscle-specific implying that each muscle possesses its own adaptive range of response to changed physiological conditions.


Characterization of transcriptome remodeling during cambium formation identifies MOL1 and RUL1 as opposing regulators of secondary growth.
Cell-to-cell communication is crucial for the development of multicellular organisms, especially during the generation of new tissues and organs. Secondary growth--the lateral expansion of plant growth axes--is a highly dynamic process that depends on the activity of the cambium. The cambium is a stem cell-like tissue whose activity is responsible for wood production and, thus, for the establishment of extended shoot and root systems. Attempts to study cambium regulation at the molecular level have been hampered by the limitations of performing genetic analyses in trees and by the difficulty of accessing this tissue in model systems such as Arabidopsis thaliana. Here, we describe the roles of two receptor-like kinases, REDUCED IN LATERAL GROWTH1 (RUL1) and MORE LATERAL GROWTH1 (MOL1), as opposing regulators of cambium activity. Their identification was facilitated by a novel in vitro system in which cambium formation is induced in isolated Arabidopsis stem fragments. By combining this system with laser capture microdissection, we characterized transcriptome remodeling in a tissue- and stage-specific manner and identified series of genes induced during different phases of cambium formation. In summary, we provide a means for investigating cambium regulation in unprecedented depth and present two signaling components that control a process responsible for the accumulation of a large proportion of terrestrial biomass.


An arginyl in the N-terminus of the V1a vasopressin receptor is part of the conformational switch controlling activation by agonist.
Defining how the agonist-receptor interaction differs from that of the antagonist-receptor and understanding the mechanisms of receptor activation are fundamental issues in cell signalling. The V1a vasopressin receptor (V1aR) is a member of a family of related G-protein coupled receptors that are activated by neurohypophysial peptide hormones, including vasopressin (AVP). It has recently been reported that an arginyl in the distal N-terminus of the V1aR is critical for binding agonists but not antagonists. To determine specific features required at this locus to support high affinity agonist binding and second messenger generation, Arg46 was substituted by all other 19 encoded amino acids. Our data establish that there is an absolute requirement for arginyl, as none of the [R46X]V1aR mutant constructs supported high affinity agonist binding and all 19 had defective signalling. In contrast, all of the mutant receptors possessed wildtype binding for both peptide and nonpeptide antagonists. The ratio of Ki to EC50, an indicator of efficacy, was increased for all substitutions. Consequently, although [R46X]V1aR constructs have a lower affinity for agonist, once AVP has bound all 19 are more likely than the wildtype V1aR to become activated. Therefore, in the wildtype V1aR, Arg46 constrains the inactive conformation of the receptor. On binding AVP this constraint is alleviated, promoting the transition to active V1aR. Our findings explain why arginyl is conserved at this locus throughout the evolutionary lineage of the neurohypophysial peptide hormone receptor family of G-protein coupled receptors.


Effects of base sequence context on translesion synthesis past a bulky (+)-trans-anti-B[a]P-N2-dG lesion catalyzed by the Y-family polymerase pol kappa.
The effects of bases flanking single bulky lesions derived from the binding of a benzo[a]pyrene 7,8-diol 9,10-epoxide derivative ((+)-7R,8S,9S,10R stereoisomer) to N(2)-guanine (G*) on translesion bypass catalyzed by the Y-family polymerase pol kappa (hDinB1) were examined in vitro. The lesions were positioned near the middle of six different 43-mer 5'-...XG*Y... sequences (X, Y = C, T, or G, with all other bases remaining fixed). The complementary dCTP is preferentially inserted opposite G* in all of the sequences; however, the proportions of other dNTPs inserted varies as a function of X and Y. The dCTP insertion efficiencies, f(ins) = (V(max)/K(m))(ins), are smaller in the XG*Y than in XGY sequences by factors of approximately 50-90 (GG*T and GG*C) or 5000-25000 (TG*G and CG*G). Remarkably, in XG*Y sequences, f(ins) varies by as much as 3 orders of magnitude, being smallest with G flanking the lesions on the 3'-side and highest with G flanking the adducts on the 5'-side. One-step primer extension efficiencies just beyond the lesions (f(ext)) are generally smaller than f(ins) and also depend on base sequence. However, reasonably efficient translesion bypass of the (+)-trans-[BP]-N(2)-dG adducts is observed in all sequences in running-start experiments with full, or nearly full, primer extension being observed under conditions of [dNTP] > K(m). The key features here are the relatively robust values of the kinetic parameters V(max) that are either diminished to a moderate extent or even enhanced in the presence of the (+)-trans-[BP]-N(2)-dG adducts. In contrast to the small effects of the lesions on V(max), the apparent K(m) values are orders of magnitude greater in XG*Y than in the unmodified XGY sequences. Thus the bypass of (+)-trans-[BP]-N(2)-dG adducts under conditions when [dNTP] < K(m) is quite inefficient. These considerations may be of importance in vivo where [dNTP] <or= K(m), and the translesion bypass of the (+)-trans-[BP]-N(2)-dG by pol kappa may be significantly less efficient than in vitro at higher dNTP concentrations. The base sequence-dependent features of translesion bypass are discussed in terms of the possible conformations of the adducts and the known structural features of bypass polymerases.


Thatcherization impacts the processing of own-race faces more so than other-race faces: an ERP study.
It has been suggested that differential use of configural processing strategies may underlie racially based recognition deficits (known as the "other-race effect"). By employing a well-known configural manipulation (Thatcherization, i.e., rotating the eyes and mouth by 180°), we aimed to demonstrate, electrophysiologically, that configural processing is used to a greater extent when viewing same-race faces than when viewing other-race faces. Face-related event-related potential (ERP) responses were measured for participants viewing normal and Thatcherized faces of their own race (Caucasian) and of another race (African-American). The P1 and N170 components were modulated to a greater extent by Thatcherization for same-race faces, suggesting that the processing of these faces is, in fact, more reliant on configural information than other-race faces. Thatcherization also affected the P250 component more so for same-race faces independently of orientation. The race-dependent effects of Thatcherization as early as P1 suggest that configural encoding may be occurring much earlier than the well-cited N170.


Seasonality of Tylenchulus semipenetrans Cobb and Pasteuria sp. in Citrus Orchards in Spain.
Population densities of the Mediterranean biotype of Tylenchulus semipenetrans were monitored in soil and citrus roots at 3-month intervals for 3 consecutive years in four citrus orchards in the provinces of Tarragona (Amposta and Xalamera) and Valencia (Moncada and Ca rcer). Nematode population densities in soil peaked once a year in April or July depending on the orchard and year. Numbers of females per gram of root increased once or twice each year. The maximum density of eggs per gram of root was recorded in April at Xalamera and Ca rcer orchards, but there was no recognizable peak in the other two orchards. Numbers of nematodes in soil, females or eggs per gram of root, or eggs per female were correlated with either temperature or rainfall in the sampling month, 1 month before sampling, or in the second preceding month, depending on the orchard. Members of the Pasteuria group were present in the four citrus orchards, and a positive relationship occurred between nematodes in soil and bacterial parasitism (r(2) = 0.75) in the orchard at Amposta.


Role of the bga1-encoded extracellular {beta}-galactosidase of Hypocrea jecorina in cellulase induction by lactose.
Lactose is the only soluble and economically feasible carbon source for the production of cellulases or heterologous proteins regulated by cellulase expression signals by Hypocrea jecorina (Trichoderma reesei). We investigated the role of the major beta-galactosidase of H. jecorina in lactose metabolism and cellulase induction. A genomic copy of the bga1 gene was cloned, and this copy encodes a 1,023-amino-acid protein with a 20-amino-acid signal sequence. This protein has a molecular mass of 109.3 kDa, belongs to glycosyl hydrolase family 35, and is the major extracellular beta-galactosidase during growth on lactose. Its transcript was abundant during growth on l-arabinose and l-arabinitol but was much less common when the organism was grown on lactose, d-galactose, galactitol, d-xylose, and xylitol. Deltabga1 strains grow more slowly and accumulate less biomass on lactose, but the cellobiohydrolase I and II gene expression and the final cellulase yields were comparable to those of the parental strain. Overexpression of bga1 under the control of the pyruvate kinase promoter reduced the lag phase, increased growth on lactose, and limited transcription of cellobiohydrolases. We detected an additional extracellular beta-galactosidase activity that was not encoded by bga1 but no intracellular beta-galactosidase activity. In conclusion, cellulase production on lactose occurs when beta-galactosidase activity levels are low but decreases as the beta-galactosidase activities increase. The data indicate that bga1-encoded beta-galactosidase activity is a critical factor for cellulase production on lactose.


Septic Shock due to Implantable Cardiac Defibrillator Related Infection.
Infection is an important complication of cardiac device implantation. We report the case of a 61 year old patient presenting with septic shock caused by cardiac device infection (CDI) three-weeks after device implantation. At initial presentation, there was an absence of both localising signs and echocardiographic evidence of CDI. Later, Staphylococcus aureus was cultured from blood and the pre-pectoral pocket. 48 hours after admission the device and leads were explanted in theatre by simple traction. Despite appropriate antibiotics and full supportive care (including haemofiltration, ventilation and inotropic support), the patient died on day six. Cardiac device infection may present with septic shock in the absence of localising features. A high index of suspicion is required, particularly for early CDI.


Relative biological effectiveness (RBE), quality factor (Q), and radiation weighting factor (w(R)). A report of the International Commission on Radiological Protection.
The effect of ionising radiation is influenced by the dose, the dose rate, and the quality of the radiation. Before 1990, dose-equivalent quantities were defined in terms of a quality factor, Q(L), that was applied to the absorbed dose at a point in order to take into account the differences in the effects of different types of radiation. In its 1990 recommendations, the ICRP introduced a modified concept. For radiological protection purposes, the absorbed dose is averaged over an organ or tissue, T, and this absorbed dose average is weighted for the radiation quality in terms of the radiation weighting factor, w(R), for the type and energy of radiation incident on the body. The resulting weighted dose is designated as the organ- or tissue-equivalent dose, H(T). The sum of the organ-equivalent doses weighted by the ICRP organ-weighting factors, w(T), is termed the effective dose, E. Measurements can be performed in terms of the operational quantities, ambient dose equivalent, and personal dose equivalent. These quantities continue to be defined in terms of the absorbed dose at the reference point weighted by Q(L). The values for w(R) and Q(L) in the 1990 recommendations were based on a review of the biological and other information available, but the underlying relative biological effectiveness (RBE) values and the choice of w(R) values were not elaborated in detail. Since 1990, there have been substantial developments in biological and dosimetric knowledge that justify a re-appraisal of w(R) values and how they may be derived. This re-appraisal is the principal objective of the present report. The report discusses in some detail the values of RBE with regard to stochastic effects, which are central to the selection of w(R) and Q(L). Those factors and the dose-equivalent quantities are restricted to the dose range of interest to radiation protection, i.e. to the general magnitude of the dose limits. In special circumstances where one deals with higher doses that can cause deterministic effects, the relevant RBE values are applied to obtain a weighted dose. The question of RBE values for deterministic effects and how they should be used is also treated in the report, but it is an issue that will demand further investigations. This report is one of a set of documents being developed by ICRP Committees in order to advise the ICRP on the formulation of its next Recommendations for Radiological Protection. Thus, while the report suggests some future modifications, the w(R) values given in the 1990 recommendations are still valid at this time. The report provides a scientific background and suggests how the ICRP might proceed with the derivation of w(R) values ahead of its forthcoming recommendations.


Publication, citations, and impact factors of leading investigators in critical care medicine.
Critical care medicine research is reported in major medical journals that can be accessed via computerized search engines such as PubMed (National Library of Medicine) or Web of Science (Thomson ISI [Institute for Scientific Information]). The crediting of report citations to specific journals or individuals is a rapidly developing and highly controversial evaluative process. We conducted a citation analysis to measure the research and publication accomplishments of critical care medicine investigators, by tallying their numbers of published reports and numbers of citations to their reports. Major investigators were identified from the author indexes of major critical care medicine publications. From the Web of Science the number of publications and citations of their works were determined for 224 investigators for the period 1997 through August 2003. We calculated the individual researcher's "impact factor" by dividing the number of citations (made by other researchers to a given researcher's reports) by the number of articles that researcher had published. To estimate which countries are producing the most research on mechanical ventilation, we studied the abstract books from the 2001, 2002, and 2003 American Thoracic Society annual international conferences and tallied the number of posters (pertaining to mechanical ventilation) from the various countries. We then calculated a "country factor" as the number of posters per million population of the source country. We considered 44, 576 citations in 3,755 publications. Using criteria selected to recognize original works, J L Vincent published the greatest number of reports (129). M A Matthay received the most citations (2,056). G U Meduri had the highest impact factor (25.32). There was a balance between the number of leading investigators from Europe and North America. Relative to its population size, Canada warrants leadership acknowledgement in critical care medicine, considering its number of leading investigators and poster presentations. From criteria selected to attribute original work to specific authors we identified 20 leading critical care medicine investigators, as measured by number of publications, citations, and impact factors. We also report a country factor based on posters (on mechanical ventilation) presented at the 2001-2003 international conferences of the American Thoracic Society.


Modeling the developmental patterns of auditory evoked magnetic fields in children.
As magnetoencephalography (MEG) is of increasing utility in the assessment of deficits and development delays in brain disorders in pediatrics, it becomes imperative to fully understand the functional development of the brain in children. The present study was designed to characterize the developmental patterns of auditory evoked magnetic responses with respect to age and gender. Sixty children and twenty adults were studied with a 275-channel MEG system. Three main responses were identified at approximately 46 ms (M50), 71 ms (M70) and 106 ms (M100) in latency for children. The latencies of M70 and M100 shortened with age in both hemispheres; the latency of M50 shortened with age only in the right hemisphere. Analysis of developmental lateralization patterns in children showed that the latency of the right hemispheric evoked responses shortened faster than the corresponding left hemispheric responses. The latency of M70 in the right hemisphere highly correlated to the age of the child. The amplitudes of the M70 responses increased with age and reached their peaks in children 12-14 years of age, after which they decreased with age. The source estimates for the M50 and M70 responses indicated that they were generated in different subareas in the Heschl's gyrus in children, while not localizable in adults. Furthermore, gender also affected developmental patterns. The latency of M70 in the right hemisphere was proposed to be an index of auditory development in children, the modeling equation is 85.72-1.240xAge (yrs). Our results demonstrate that there is a clear developmental pattern in the auditory cortex and underscore the importance of M50 and M70 in the developing brain.


A computational framework for the inheritance pattern of genomic imprinting for complex traits.
Genetic imprinting, by which the expression of a gene depends on the parental origin of its alleles, may be subjected to reprogramming through each generation. Currently, such reprogramming is limited to qualitative description only, lacking more precise quantitative estimation for its extent, pattern and mechanism. Here, we present a computational framework for analyzing the magnitude of genetic imprinting and its transgenerational inheritance mode. This quantitative model is based on the breeding scheme of reciprocal backcrosses between reciprocal F(1) hybrids and original inbred parents, in which the transmission of genetic imprinting across generations can be tracked. We define a series of quantitative genetic parameters that describe the extent and transmission mode of genetic imprinting and further estimate and test these parameters within a genetic mapping framework using a new powerful computational algorithm. The model and algorithm described will enable geneticists to identify and map imprinted quantitative trait loci and dictate a comprehensive atlas of developmental and epigenetic mechanisms related to genetic imprinting. We illustrate the new discovery of the role of genetic imprinting in regulating hyperoxic acute lung injury survival time using a mouse reciprocal backcross design.


Differentiation of movement behaviour in an adaptively diverging salamander population.
Dispersal is considered to be a species-specific trait, but intraspecific variation can be high. However, when and how this complex trait starts to differentiate during the divergence of species/lineages is unknown. Here, we studied the differentiation of movement behaviour in a large salamander population (Salamandra salamandra), in which individual adaptations to different habitat conditions drive the genetic divergence of this population into two subpopulations. In this system, salamanders have adapted to the deposition and development of their larvae in ephemeral ponds vs. small first-order streams. In general, the pond habitat is characterized as a spatially and temporally highly unpredictable habitat, while streams provide more stable and predictable conditions for the development of larvae. We analysed the fine-scale genetic distribution of larvae, and explored whether the adaptation to different larval habitat conditions has in turn also affected dispersal strategies and home range size of adult salamanders. Based on the genetic assignment of adult individuals to their respective larval habitat type, we show that pond-adapted salamanders occupied larger home ranges, displayed long-distance dispersal and had a higher variability of movement types than the stream-adapted individuals. We argue that the differentiation of phenotypically plastic traits such as dispersal and movement characteristics can be a crucial component in the course of adaptation to new habitat conditions, thereby promoting the genetic divergence of populations.


Motor coordination in children with congenital strabismus: effects of late surgery.
Strabismus is one of the most common visual disorders in infancy. While there is a great attention on the effects of the timing of surgery as to the development of binocular vision, little is known about the possible influence of congenital strabismus on perceptual-motor and more generally, on neuromotor development. Aim of this study was to investigate perceptual-motor and motor coordination abilities of 19 children with essential congenital esotropia who underwent a late surgery (after 4 years), compared to 23 age-matched controls. Children were tested using the Movement Assessment Battery for Children (Movement ABC) that were performed both 1-week before surgery (T1) and about 3 months (+/-2 weeks) after surgery (T2). At T1, abnormal or borderline results were found in more than half of the children with strabismus, as opposed to only about 17% of the controls. At T2 none of the children showed abnormal Movement ABC total scores and there was no difference in global scores between the study and the control group. The two groups also did not show any significant difference in individual items of the movement ABC with the exception of those assessing ball skills. Our results suggest that surgical correction of strabismus, even when performed after the 4th year of life, appears to be effective in improving perceptual-motor and motor function.


Gold strip gratings with binary supercell.
In this Letter, the study of a periodic structure composed of gold strips arranged in double-period unit cells, in a symmetric and asymmetric environment, is reported. The spectral maps show that the formation of the plasmonic bandgap and the extraordinary optical transmission are subjected to the proportion between the strip widths. Moreover, when the asymmetric environment is considered, high-transmittance and high-absorbance states arise. Hence, by controlling the geometrical parameters of the binary-periodic structure, it is possible to tailor the spectral response of the grating enhancing the desired features and exploiting them for different applications.


Rehabilitation of a maxillectomy patient using intraoral scanning impression technology and a computer-aided design/computer-aided manufacturing fabricated obturator prosthesis: A clinical report.
Rehabilitation of a partially dentate postmaxillectomy patient using a novel approach is presented in this report. The patient was referred to our practice by the oral and maxillofacial surgery department of the local general hospital for the evaluation and prosthetic treatment planning. He had undergone biopsy for a lesion located in the right quadrant of his maxilla and was scheduled for a hemimaxillectomy for removal of a squamous cell carcinoma. A surgical obturator was prepared for placement at the time of ablative surgery. Following completion of adjuvant radiotherapy and chemotherapy, a digital intraoral impression of the remaining maxilla and mandible was obtained, and a computer-aided design/computer-aided manufacturing obturator removable partial denture utilizing a selective laser melting -produced metal framework was fabricated and delivered to the patient to restore function and esthetics. The need for conventional impression was eliminated leading to a reduction of necessary appointments and more comfort to the patient.


The effects of mindfulness-based interventions on nursing students: A meta-analysis.
Recently, mindfulness interventions have been extensively applied in the field of nursing education. However, no consensus has been reached on whether these interventions can reduce anxiety and depression in nursing students. This meta-analysis was designed to determine the effect of mindfulness interventions on levels of depression, anxiety, stress and mindfulness for nursing students. Meta-analysis of randomized controlled trials. The following Chinese and English databases were searched for relevant articles: Pubmed, Embase, Cochrane library, Web of Science, CNKI (China National Knowledge Infrastructure) and Wanfang. The search encompassed the establishment of these databases up until January 2020. Two reviewers separately entered the data into Review Manager Software 5.3. A total of 10 randomized controlled trials (RCTs) were reviewed. It was found that mindfulness interventions significantly lowered levels of depression (SMD = -0.42, 95% CI:-0.56 to -0.28, P < 0.001), anxiety (SMD = -0.32, 95% CI:-0.47 to -0.17, P < 0.001) and stress (SMD = -0.50, 95% CI:-0.65 to -0.35, P < 0.001) in nursing students. Furthermore, the interventions raised levels of mindfulness in this group (SMD = 0.54, 95% CI:0.33-0.75, P < 0.001). Mindfulness interventions can significantly reduce nursing students' negative emotions, helping them to manage their stress and anxiety. College nursing educators should consider adopting mindfulness interventions in nursing education to promote the mental health of students.


An empirical study of defense mechanisms. I. Clinical interview and life vignette ratings.
The Defense Mechanism Rating Scales (DMRS) measure the use of defense mechanisms based on clinical interview or life vignette data. Using nonprofessional raters observing videotaped psychodynamic interviews of individuals with personality and affective disorders, the median intraclass interrater reliability (IR) of the defense scales was .36 but was .57 for group consensus ratings and .74 when related defenses were grouped into defense summary scales. When follow-up data on life vignettes were rated, the median interrater IR was .55 for those defenses occurring at least 5% of the time and .66 for the defense summary scales. In relation to follow-up data, so-called immature defenses (denial, projection, acting out, hypochondriasis, passive-aggression) were associated with higher levels of symptoms, poorer global functioning, and higher proportion of time impaired in psychosocial role functioning. Borderline defenses (splitting, projective identification) displayed a similar pattern. Among narcissistic and neurotic defenses, only devaluation was associated with poorer functioning, whereas intellectualization was associated with higher functioning. Finally, action and borderline defenses demonstrated significant correlations across methods and across time (video vs life vignettes), whereas obsessional, disavowal, and narcissistic defenses showed nonsignificant trends. Overall, these results support the model of a hierarchy of defenses.


A psychometric analysis of the measurement level of the rating scale, time trade-off, and standard gamble.
A fundamental assumption of utility-based analyses is that patient utilities for health states can be measured on an equal-interval scale. This assumption, however, has not been widely examined. The objective of this study was to assess whether the rating scale (RS), standard gamble (SG), and time trade-off (TTO) utility elicitation methods function as equal-interval level scales. We wrote descriptions of eight prostate-cancer-related health states. In interviews with patients who had newly diagnosed, advanced prostate cancer, utilities for the health states were elicited using the RS, SG, and TTO methods. At the time of the study, 77 initial and 73 follow-up interviews had. been conducted with a consecutive sample of 77 participants. Using a Rasch model, the boundaries (Thurstone Thresholds) between four equal score sub-ranges of the raw utilities were mapped onto an equal-interval logit scale. The distance between adjacent thresholds in logit units was calculated to determine whether the raw utilities were equal-interval. None of the utility scales functioned as interval-level scales in our sample. Therefore, since interval-level estimates are assumed in utility-based analyses, doubt is raised regarding the validity of findings from previous analyses based on these scales. Our findings need to be replicated in other contexts, and the practical impact of non-interval measurement on utility-based analyses should be explored. If cost-effectiveness analyses are not found to be robust to violations of the assumption that utilities are interval, serious doubt will be cast upon findings from utility-based analyses and upon the wisdom of expending millions in research dollars on utility-based studies.


Anthropological measurement of lower limb and foot bones using multi-detector computed tomography.
Anthropological examination of defleshed bones is the gold standard for osteological measurement in forensic practice. However, multi-detector computed tomography (MDCT) offers the opportunity of three-dimensional imaging of skeletal elements, allowing measurement of bones in any plane without defleshing. We present our experiences of the examination of 15 human lower limbs in different states of decomposition using MDCT. We present our method of imaging and radiological measurement of the bones including sex assessment. The radiological measurements were undertaken by three professional groups--anthropology, radiology, and forensic pathology--both at the site of scanning and at a remote site. The results were compared to anthropological oestological assessment of the defleshed bones. We discuss the limitations of this technique and the potential applications of our observations. We introduce the concept of remote radiological anthropological measurement of bones, so-called tele-anthro-radiology and the role that this could play in providing the facility for standardization of protocols, international peer review and quality assurance schemes.


Single and Combined Impacts of Vitamin A and Selenium in Diet on Productive Performance, Egg Quality, and Some Blood Parameters of Laying Hens During Hot Season.
A study was conducted using 162 Bovans laying hens to investigate the impacts of extra dietary vitamin A (0, 8000, 16,000 IU/kg), selenium (0, 0.25, 0.50 mg/kg), and their combinations on the performance, egg quality, and blood biological parameters of laying hens during summer months. Supplemental vitamin A up to 16,000 IU/kg diet significantly (P < 0.05) improved all productive traits studied except feed intake which increased with 8000 IU/kg diet compared with control. Feed intake and feed conversion of hens fed diet supplemented with selenium revealed high statistical (P = 0.001) differences. All egg quality criteria were not significantly (P < 0.05) affected by dietary vitamin A except albumin percentage and Haugh units, since Haugh unit score was gradually increased with increasing vitamin A level. Vitamin A-enriched groups showed significant (P < 0.05 and 0.01) decreases in plasma albumen, total lipids, and total cholesterol in respect to the unsupplemented groups. Compared with unsupplemented groups, total protein, albumin, total lipid, and total cholesterol were increased in selenium-enriched groups. There were no significant impacts of selenium treatments in layer diets on thyroid hormones and liver enzymes studied except alanine transferase (ALT) and thyroxin (T4), as compared with the control group. Hematological parameters were not affected by vitamin A treatment except PCV% which decreased with vitamin A supplementation. Hemoglobin and lymphocytes were increased with increasing dietary selenium level. In conclusion, the combined supplementary concentrations of vitamin A (16,000 IU/kg) and selenium (0.25 mg/kg) might be needed for better production and health of laying hens reared under heat stress conditions.


Germline BAP1-positive patients: the dilemmas of cancer surveillance and a proposed interdisciplinary consensus monitoring strategy.
The germline BAP1 (BRCA1-associated protein-1) mutation and associated cancer pre-disposition syndrome was first described in 2011. Since then, physicians have considered this diagnosis for patients with a characteristic personal or family history of BAP1-associated tumours (mainly uveal and cutaneous melanoma, pleural/peritoneal mesothelioma, renal cell carcinoma and BAP1-deficient melanocytic lesions). However, a positive germline BAP1 mutation detection creates significant uncertainty in terms of appropriate cancer surveillance. A number of groups have proposed surveillance plans but important management dilemmas remain unresolved. The lifetime risk of developing cancer is not known and it is not clear if surveillance would lead to detecting cancer at an earlier stage or change survival outcomes. A consensus monitoring strategy was initially proposed at the Melanoma Institute Australia Melanoma Multidisciplinary Team meeting and later discussed with specialists in the field of cancer genetics, pathology, radiology, medical oncology, ophthalmology and dermatology. The objectives were to facilitate early diagnosis, incorporating where possible, clinically based and low/non-ionising radiation imaging modalities, applying the principles of a good screening test and a multidisciplinary focus.


Balance, falls, and bone health: role of exercise in reducing fracture risk after stroke.
Fractures occur frequently in people living with stroke and have high personal, social, and economic costs for these individuals, their families, and the community. Exercise to reduce the risk of fragility fractures is a relatively new application in stroke rehabilitation but is a promising treatment with the potential to reduce the incidence of falls as well as maintain or improve bone health. In this article, we outline fracture risk factors and provide an overview of exercise interventions aimed at reducing fracture risk poststroke. Although randomized controlled trials support the use of exercise to reduce fracture risk factors poststroke, the body of literature is small and further studies are required. Further, the optimal dose of exercise and the additive effects of pharmacology on fracture risk need to be determined. Given the many health benefits associated with exercise, it should be considered an important modality for the management of falls and maintenance of bone health following stroke.


Cutaneous Anthrax on Eyelid in a Pregnant Woman.
A 32-year-old patient who was 17 weeks of pregnant referred to our hospital due to a lesion on the eyelid and swelling on her face. Patient's history revealed that she helped her husband for slaughtering of a sick animal and contacted with the meat. A scabby lesion was detected on the inferior eyelid with hyperaemia around, central necrotic appearance and swelling. The diagnosis of anthrax was performed based on her epidemiological data, physical examination findings, and Bacillus anthracis were seen on direct preparation. This case was considered worthy to present since she was pregnant, the disease was located on the inferior eyelid, which is a rare place for location, and caused no complication or sequel either in mother or in baby.


What determines the current presence or absence of permafrost in the Torneträsk region, a sub-arctic landscape in northern Sweden?
In a warming climate, permafrost is likely to be significantly reduced and eventually disappear from the sub-Arctic region. This will affect people at a range of scales, from locally by slumping of buildings and roads, to globally as melting of permafrost will most likely increase the emissions of the powerful greenhouse gas methane, which will further enhance global warming. In order to predict future changes in permafrost, it is crucial to understand what determines the presence or absence of permafrost under current climate conditions, to assess where permafrost is particularly vulnerable to climate change, and to identify where changes are already occurring. The Torneträsk region of northern sub-Arctic Sweden is one area where changes in permafrost have been recorded and where permafrost could be particularly vulnerable to any future climate changes. This paper therefore reviews the various physical, biological, and anthropogenic parameters that determine the presence or absence of permafrost in the Torneträsk region under current climate conditions, so that we can gain an understanding of its current vulnerability and potential future responses to climate change. A patchy permafrost distribution as found in the Torneträsk region is not random, but a consequence of site-specific factors that control the microclimate and hence the surface and subsurface temperature. It is also a product of past as well as current processes. In sub-Arctic areas such as northern Sweden, it is mainly the physical parameters, e.g., topography, soil type, and climate (in particular snow depth), that determine permafrost distribution. Even though humans have been present in the study area for centuries, their impacts on permafrost distribution can more or less be neglected at the catchment level. Because ongoing climate warming is projected to continue and lead to an increased snow cover, the permafrost in the region will most likely disappear within decades, at least at lower elevations.


Protein turnover, synthesis and breakdown before and after recovery from protein-energy malnutrition.
1. Rates of total protein turnover, synthesis and breakdown were measured in five children before and after recovery from severe protein-energy malnutrition and while receiving 0.6 g of protein and 397 kJ day-1 kg-1. 2. Thes rates were calculated after giving doses of [15N]glycine every 2 h along with the feeds and measuring the rate of excretion of [15N]urea in urine. 3. Malnourished children had significantly lower rates of protein turnover, synthesis and breakdown than after they had recovered. 4. During recovery from protein-energy malnutrition, two children on a daily intake of 1.2 g of protein and 605 J/kg body weight, had rates of protein turnover, synthesis and breakdown that were twice as great as those found on admission and higher than after recovery. 5. On the study diet the malnourished children maintained their weight while the recovered children lost weight; the apparent nitrogen balance was more positive in the malnourished children. 6. In recovered children, the rate of protein synthesis was unchanged over a wide range of protein intake, whereas the rate of protein breakdown appeared to rise with a reduction in protein intake.


CD81 and claudin 1 coreceptor association: role in hepatitis C virus entry.
Hepatitis C virus (HCV) is an enveloped positive-stranded RNA hepatotropic virus. HCV pseudoparticles infect liver-derived cells, supporting a model in which liver-specific molecules define HCV internalization. Three host cell molecules have been reported to be important entry factors or receptors for HCV internalization: scavenger receptor BI, the tetraspanin CD81, and the tight junction protein claudin-1 (CLDN1). None of the receptors are uniquely expressed within the liver, leading us to hypothesize that their organization within hepatocytes may explain receptor activity. Since CD81 and CLDN1 act as coreceptors during late stages in the entry process, we investigated their association in a variety of cell lines and human liver tissue. Imaging techniques that take advantage of fluorescence resonance energy transfer (FRET) to study protein-protein interactions have been developed. Aequorea coerulescens green fluorescent protein- and Discosoma sp. red-monomer fluorescent protein-tagged forms of CD81 and CLDN1 colocalized, and FRET occurred between the tagged coreceptors at comparable frequencies in permissive and nonpermissive cells, consistent with the formation of coreceptor complexes. FRET occurred between antibodies specific for CD81 and CLDN1 bound to human liver tissue, suggesting the presence of coreceptor complexes in liver tissue. HCV infection and treatment of Huh-7.5 cells with recombinant HCV E1-E2 glycoproteins and anti-CD81 monoclonal antibody modulated homotypic (CD81-CD81) and heterotypic (CD81-CLDN1) coreceptor protein association(s) at specific cellular locations, suggesting distinct roles in the viral entry process.


X-ray microtomography-based measurements of meniscal allografts.
X-ray microcomputed tomography (XMT) is a technique widely used to image hard and soft tissues. Meniscal allografts as collagen structures can be imaged and analyzed using XMT. The aim of this study was to present an XMT scanning protocol that can be used to obtain the 3D geometry of menisci. It was further applied to compare two methods of meniscal allograft measurement: traditional (based on manual measurement) and novel (based on digital measurement of 3D models of menisci obtained with use of XMT scanner). The XMT-based menisci measurement is a reliable method for assessing the geometry of a meniscal allograft by measuring the basic meniscal dimensions known from traditional protocol. Thirteen dissected menisci were measured according the same principles traditionally applied in a tissue bank. Next, the same specimens were scanned by a laboratory scanner in the XMT Lab. The images were processed to obtain a 3D mesh. 3D models of allograft geometry were then measured using a novel protocol enhanced by computer software. Then, both measurements were compared using statistical tests. The results showed significant differences (P<0.05) between the lengths of the medial and lateral menisci measured in the tissue bank and the XMT Lab. Also, medial meniscal widths were significantly different (P<0.05). Differences in meniscal lengths may result from difficulties in dissected meniscus measurements in tissue banks, and may be related to the elastic structure of the dissected meniscus. Errors may also be caused by the lack of highlighted landmarks on the meniscal surface in this study. The XMT may be a good technique for assessing meniscal dimensions without actually touching the specimen.


Antibiofilm coatings based on protein-engineered polymers and antimicrobial peptides for preventing implant-associated infections.
Implant-associated infections (IAIs) are one of the leading concerns in orthopedics and dentistry as they commonly lead to implant failure. The presence of biofilms and, increasingly frequently, drug-resistant bacteria further impairs the efficacy of conventional antibiotics. Immobilization of antimicrobial peptides (AMPs) on implant surfaces is a promising alternative to antibiotics for prevention of IAIs. In addition, the use of functional linkers for the AMP tethering enables to increase the antimicrobial potential and the bioactivities of the coating. In this study, an extracellular-matrix-mimicking system based on elastin-like recombinamers (ELRs) has been developed for the covalent anchoring of AMPs and investigated for use as a hybrid antibiofilm coating. A drip-flow biofilm reactor was used to simulate in vivo environmental dynamic conditions, thus showing that the presence of the AMPs in the hybrid coatings provided strong antibiofilm activity against monospecies and microcosm biofilm models of clinical relevance. These results, together with an excellent cytocompatibility towards primary gingival fibroblasts, encourage the use of ELRs as multivalent platforms for AMPs and open up a wide range of possibilities in the biofabrication of advanced coatings combining the antibiofilm potential of AMPs and the outstanding tunability and biomechanical properties of the ELRs.


Long-term assessment of auditory changes resulting from a single noise exposure associated with non-occupational activities.
We examined the long-term sequelae in both ears of 42 patients who reported the occurrence of auditory changes resulting from a single exposure to intense sound levels during non-occupational activities. We divided these patients into two groups, based upon noise exposures of either continuous duration or single high-energy impulse. Audiometric data were available for each of these subjects shortly after their noise-exposure events and follow-up examinations took place more than one year after the noise occurrence (range: 1-16 years). The initial median hearing loss for the continuous-type noise exposure group at 3-8 kHz was found to be 9 dB, relative to the age-appropriate norms, in the more affected ears, and hearing function was found to have returned to normal levels at follow-up. The same initial hearing loss was measured for the impulse-type noise group, but a residual hearing loss of 4 dB was measured at follow-up. Furthermore, the majority of the subjects from both groups reported tinnitus and hypersensitivity to sound at follow-up, but with minimal impact on their lives.


Comprehensive Format of Informed Consent in Research and Practice: A Tool to uphold the Ethical and Moral Standards.
Informed consent in research, clinical trial, and practice is a process in which a patient/participant consents to participate or undergo the proposed procedures after being informed of its procedures, risks, and benefits. Ideally, the patient/participant is expected to give his consent only after fully comprehending the information about the procedures, benefits, and risks involved in research/clinical trial/practice. Thus, many ethical issues are entwined in the process of obtaining a proper informed consent. Certain untoward events in the past led to propose guidelines to prevent exploitations and unhealthy practices in the field of life science. Eventually, the practice of obtaining informed consent was emphasized to make sure that a participant's rights were not in jeopardy. Yet, there are flaws in the practical application of obtaining consent due to lack of understanding, barriers in communication, culture, custom, and various other factors. The present article highlights the need for a complete and comprehensive format of recording informed consent without compromising the rights of an individual and the standards of research or practice on ethical and moral grounds. Bhupathi PA, Ravi GR. Comprehensive Format of Informed Consent in Research and Practice: A Tool to uphold the Ethical and Moral Standards. Int J Clin Pediatr Dent 2017;10(1):73-81.


Structure and stability of X.G.C mismatches in the third strand of intramolecular triplexes.
Intramolecular DNA triplexes that contain eight base triplets formed from the folding of a single DNA strand tolerate a single X.G.C mismatch in the third strand at acidic pH. The structure and relative stability of all four triplets that are possible involving a G.C Watson-Crick base pair were determined with one- and two-dimensional proton nuclear magnetic resonance techniques. Triplexes containing A.G.C, G.G.C, or T.G.C triplets were less stable than the corresponding parent molecule containing a C.G.C triplet. However, all mismatched bases formed specific hydrogen bonds in the major groove of the double helix. The relative effect of these mismatches on the stability of the triplex differs from the effect assayed (under different conditions) by two-dimensional gel electrophoresis and DNA cleavage with oligonucleotide EDTA.Fe(II).


Classification and analysis of the errors in neuronavigation.
There are many different types of errors in neuronavigation, and the reasons and results of these errors are complex. For a neurosurgeon using the neuronavigation system, it is important to have a clear understanding of when an error may occur, what the magnitude of it is, and how to avoid it or reduce its influence on the final application accuracy. In this article, we classify all the errors into 2 groups according to the working principle of neuronavigation systems. The first group contains the errors caused by the differences between the anatomic structures in the images and that of the real patient, and the second group contains the errors occurring in transforming the position of surgical tools from the patient space to the image space. Each group is further divided into 2 subgroups. We discuss 16 types of errors and classify each of them into one of the subgroups. The classification and analysis of these errors should help neurosurgeons understand the power and limits of neuronavigation systems and use them more properly.


Clinical outcome and quality of life assessment in patients treated with perineal urethrostomy for anterior urethral stricture disease.
We performed a quality of life assessment for patients treated with perineal urethrostomy for anterior urethral stricture disease. We retrospectively reviewed 173 patients (median age 55 years) who underwent perineal urethrostomy (from 1978 to 2007) as part of a plan for a staged urethroplasty repair for a complex anterior urethral stricture. The perineostomy was made using flap urethroplasty. The clinical outcome was considered a failure when postoperative instrumentation was needed. A questionnaire was used to evaluate patient quality of life and satisfaction. Stricture etiology was unknown in 50.3% of the cases, lichen sclerosus in 17.3%, catheter in 13.3%, instrumentation in 8.7%, failed hypospadias repair in 4.6%, trauma in 4.1% and infection in 1.7%. Stricture length was 1 to less than 2 cm in 1.2% of cases, 2 to less than 3 cm in 3.5%, 3 to less than 4 cm in 12.1%, 4 to less than 5 cm in 13.8%, 5 to less than 6 cm in 7.5%, greater than 6 cm in 4.1% and panurethral in 57.8%. Of 173 patients 91 (52.6%) underwent prior urethroplasty. Median followup length was 62 months (range 12 to 361). Of 173 cases 121 (70%) were successful and 52 (30%) were failures, requiring revision of the perineostomy. Of 173 patients 135 (78%) were satisfied with the results obtained with surgery, 33 (19.1%) were very satisfied, 127 (73.4%) with a median age of 57 years (range 23 to 85) refused to do the second stage of urethroplasty and 46 (26.6%) with a median age of 47.5 years (range 27 to 72) are currently on a waiting list for the second stage of urethroplasty. Perineostomy is a necessary procedure for patients with complex urethral pathology and satisfaction rates are high.


Collective dynamics of self-propelled semiflexible filaments.
The collective behavior of active semiflexible filaments is studied with a model of tangentially driven self-propelled worm-like chains. The combination of excluded-volume interactions and self-propulsion leads to several distinct dynamic phases as a function of bending rigidity, activity, and aspect ratio of individual filaments. We consider first the case of intermediate filament density. For high-aspect-ratio filaments, we identify a transition with increasing propulsion from a state of free-swimming filaments to a state of spiraled filaments with nearly frozen translational motion. For lower aspect ratios, this gas-of-spirals phase is suppressed with growing density due to filament collisions; instead, filaments form clusters similar to self-propelled rods. As activity increases, finite bending rigidity strongly effects the dynamics and phase behavior. Flexible filaments form small and transient clusters, while stiffer filaments organize into giant clusters, similarly to self-propelled rods, but with a reentrant phase behavior from giant to smaller clusters as activity becomes large enough to bend the filaments. For high filament densities, we identify a nearly frozen jamming state at low activities, a nematic laning state at intermediate activities, and an active-turbulence state at high activities. The latter state is characterized by a power-law decay of the energy spectrum as a function of wave number. The resulting phase diagrams encapsulate tunable non-equilibrium steady states that can be used in the organization of living matter.


How do early career health sciences information professionals gain competencies?
The purpose of this study was to describe early career health sciences information professionals' self-reported attainment of the Medical Library Association (MLA) Competencies for Lifelong Learning and Professional Success and to investigate the various methods by which participants developed these competencies. A SurveyMonkey survey was designed to ascertain participants' demographic information and their competency attainment. "Early career" health information professionals were defined as those with less than five years of professional experience. Participants were asked to rate each of the seven competencies on a five-point Likert scale regarding their level of agreement with the statement, "I have demonstrated this competency." Participants who responded positively were then asked to indicate how they acquired the competency on a multiple-choice, multiple-answer list. Free-text fields were provided for general comments and for participants to elaborate on their answers. The survey was distributed through the MLA email discussion list and other related email discussion lists. Participation was anonymous. One hundred eighty-seven responses were received. Out of those 187 respondents, 95 completed the entire survey. The majority of early career health sciences information professionals agreed that they had attained all 7 competencies. Of the various methods used to develop competencies, the most selected method was formal library and information studies education. Participants were least likely to report attaining competencies via mentoring, volunteering, or internships. Participants reported the highest level of confidence in having attained the "Health Sciences Information Services" competency, and the lowest level of confidence in having attained the "Research, Analysis, and Interpretation" competency. These results contribute to the ongoing discussions regarding proposed changes to the MLA competencies. The results may also inform the development of educational and professional development opportunities for prospective or early career health information professionals.


The robust australopithecine face: a morphogenetic perspective.
The robust australopithecines were a side branch of human evolution. They share a number of unique craniodental features that suggest their monophyletic origin. However, virtually all of these traits appear to reflect a singular pattern of nasomaxillary modeling derived from their unusual dental proportions. Therefore, recent cladistic analyses have not resolved the phylogenetic history of these early hominids. Efforts to increase cladistic resolution by defining traits at greater levels of anatomical detail have instead introduced substantial phyletic error.


Blalock-Taussig shunt: experience from the developing world.
Palliative procedures have a role in congenital cardiac malformations that do not permit a complete early repair, and in centres where facilities for complete early repair do not exist. The lack of data on modified Blalock-Taussig shunt from developing countries prompted this analysis. We report a retrospective study of 70 Blalock-Taussig shunt procedures in 63 patients over an 8-year period. Most of the procedures (54.0%) were done on children less than 4 months of age. Thirty-nine (58%) patients had Tetralogy of Fallot; the remaining patients had a wide spectrum of lesions. In the first year of the review period, the classical Blalock-Taussig shunt was done in six patients (9.5%) and the modified Blalock-Taussig shunt was used thereafter. In 49 patients who were followed up long term, clinical congestive cardiac failure developed in three (6%) and shunt failure was reported in 10 (14%). Of the 16 (33%) total deaths, six had serious comorbid conditions preoperatively. The Blalock-Taussig shunt is a relatively safe palliative procedure, requiring fewer resources and less expertise than corrective surgery, making it a suitable option in developing countries.


Risk of cryptorchidism among sons of horticultural workers and farmers in Denmark.
Previous studies indicate an increased risk of cryptorchidism, incomplete testicular descent, among sons of women working with pesticides. This study assessed the risk of cryptorchidism among boys of parents employed as horticultural workers and farmers using nationwide registers on occupation and cryptorchidism. The cohort consisted of >600 000 boys born in Denmark from 1980-2007 with a parent in employment during pregnancy. These boys were followed for cryptorchidism from 1980-2009 comparing risks among sons of horticultural workers and farmers with sons of parents in other occupations. Hazard ratios (HR) and 95% confidence intervals (95% CI) were estimated using Cox regression adjusting for parental age, birth years, parity, and geographical region. Sons of maternal farmers were at increased risk of cryptorchidism (157 cases; HR 1.31, 95% CI 1.12-1.53) compared to boys of mothers in other occupations (15 511 cases). Paternal occupation as farmer was unrelated to the risk among sons. Maternal occupation as a horticultural worker was associated with a non-significantly increased risk (72 cases; HR 1.20, 95% CI 0.95-1.52). A similar association was found for paternal horticultural workers. Sons of maternal farmers or horticultural workers who likely worked in the first trimester were not at increased risk of cryptorchidism. This nationwide cohort study found a slightly increased risk of cryptorchidism in sons of maternal horticultural workers and farmers. However, subgroup analyses indicated similar findings for paternal horticultural workers, and no association for women likely working in the first trimester. The main findings should therefore be interpreted with caution.


Relative intake of macronutrients impacts risk of mild cognitive impairment or dementia.
High caloric intake has been associated with an increased risk of cognitive impairment. Total caloric intake is determined by the calories derived from macronutrients. The objective of the study was to investigate the association between percent of daily energy (calories) from macronutrients and incident mild cognitive impairment (MCI) or dementia. Participants were a population-based prospective cohort of elderly persons who were followed over a median 3.7 years (interquartile range, 2.5-3.9) of follow-up. At baseline and every 15 months, participants (median age, 79.5 years) were evaluated using the Clinical Dementia Rating scale, a neurological evaluation, and neuropsychological testing for a diagnosis of MCI, normal cognition, or dementia. Participants also completed a 128-item food-frequency questionnaire at baseline; total daily caloric and macronutrient intakes were calculated using an established database. The percent of total daily energy from protein (% protein), carbohydrate (% carbohydrate), and total fat (% fat) was computed. Among 937 subjects who were cognitively normal at baseline, 200 developed incident MCI or dementia. The risk of MCI or dementia (hazard ratio, [95% confidence interval]) was elevated in subjects with high % carbohydrate (upper quartile: 1.89 [1.17-3.06]; p for trend = 0.004), but was reduced in subjects with high % fat (upper quartile: 0.56 [0.34-0.91]; p for trend = 0.03), and high % protein (upper quartile 0.79 [0.52-1.20]; p for trend = 0.03) in the fully adjusted models. A dietary pattern with relatively high caloric intake from carbohydrates and low caloric intake from fat and proteins may increase the risk of MCI or dementia in elderly persons.


Exact results for noise power spectra in linear biochemical reaction networks.
We present a simple method for determining the exact noise power spectra and related statistical properties for linear chemical reaction networks. The method is applied to reaction networks which are representative of biochemical processes such as gene expression. We find, for example, that a post-translational modification reaction can reduce the noise associated with gene expression. Our results also indicate how to coarse grain networks by the elimination of fast reactions. In this context we have discovered a breakdown of the sum rule which relates the noise power spectrum to the total noise. The breakdown can be quantified by a sum rule deficit, which is found to be universal, and can be attributed to the high-frequency noise in the fast reactions.


The Dorsal 4-finger Technique: A Novel Method to Examine Metacarpophalangeal Joints in Patients with Rheumatoid Arthritis.
To describe the dorsal 4-finger technique (DFFT) in examining metacarpophalangeal (MCP) joints of patients with rheumatoid arthritis (RA) and compare it to the traditional 2-finger technique (TFT) using ultrasound (US) as a gold standard. Four rheumatologists evaluated 180 MCP joints of 18 patients with RA. All patients underwent US for greyscale (GSUS) and power Doppler US (PDUS). Agreements between rheumatologists, the 2 techniques, and US were evaluated using Cohen κ and the first-order agreement coefficient (AC1) κ methods. The population comprised 17 females (94.4%) with a mean (SD) age and disease duration of 56.8 (14.4) and 21.8 (12.9) years, respectively. Eight patients (44.4%) were taking methotrexate monotherapy, while 10 patients (55.6%) were receiving biologics. US evaluation revealed 69 (38.3%) and 30 (16.7%) joints exhibited synovitis grade 2-3 by GSUS and PDUS, respectively. Effusion was documented in 30 joints (16.7%). The mean intraobserver agreement using the DFFT and TFT were 80.5% and 86%, respectively. The mean interobserver agreements using the DFFT and TFT were 84% and 74%, respectively. κ agreement with US findings was similar for both techniques in tender joints but was higher for the DFFT in nontender joints (0.33 vs 0.07, p = 0.015 for GSUS) and (0.48 vs 0.11, p = 0.002 for PDUS). The DFFT had a higher sensitivity in detecting ballottement by GSUS (0.47 vs 0.2, p < 0.001) and PDUS (0.60 vs 0.27, p < 0.001). The DFFT is a novel, reproducible, and reliable method to examine MCP joints, and it has a better correlation with US than the traditional TFT.


Levels of processing during non-conscious perception: a critical review of visual masking.
Understanding the extent and limits of non-conscious processing is an important step on the road to a thorough understanding of the cognitive and cerebral correlates of conscious perception. In this article, we present a critical review of research on subliminal perception during masking and other related experimental conditions. Although initially controversial, the possibility that a broad variety of processes can be activated by a non-reportable stimulus is now well established. Behavioural findings of subliminal priming indicate that a masked word or digit can have an influence on perceptual, lexical and semantic levels, while neuroimaging directly visualizes the brain activation that it evokes in several cortical areas. This activation is often attenuated under subliminal presentation conditions compared to consciously reportable conditions, but there are sufficiently many exceptions, in paradigms such as the attentional blink, to indicate that high activation, per se, is not a sufficient condition for conscious access to occur. We conclude by arguing that for a stimulus to reach consciousness, two factors are jointly needed: (i) the input stimulus must have enough strength (which can be prevented by masking) and (ii) it must receive top-down attention (which can be prevented by drawing attention to another stimulus or task). This view leads to a distinction between two types of non-conscious processes, which we call subliminal and preconscious. According to us, maintaining this distinction is essential in order to make sense of the growing neuroimaging data on the neural correlates of consciousness.


From molecules to dynamic biological communities.
Microbial ecology is flourishing, and in the process, is making contributions to how the ecology and biology of large organisms is understood. Ongoing advances in sequencing technology and computational methods have enabled the collection and analysis of vast amounts of molecular data from diverse biological communities. While early studies focused on cataloguing microbial biodiversity in environments ranging from simple marine ecosystems to complex soil ecologies, more recent research is concerned with community functions and their dynamics over time. Models and concepts from traditional ecology have been used to generate new insight into microbial communities, and novel system-level models developed to explain and predict microbial interactions. The process of moving from molecular inventories to functional understanding is complex and challenging, and never more so than when many thousands of dynamic interactions are the phenomena of interest. We outline the process of how epistemic transitions are made from producing catalogues of molecules to achieving functional and predictive insight, and show how those insights not only revolutionize what is known about biological systems but also about how to do biology itself. Examples will be drawn primarily from analyses of different human microbiota, which are the microbial consortia found in and on areas of the human body, and their associated microbiomes (the genes of those communities). Molecular knowledge of these microbiomes is transforming microbiological knowledge, as well as broader aspects of human biology, health and disease.


Peripheral arterial disease and risk of hip fracture: A systematic review and meta-analysis of cohort studies.
Previous studies have suggested an increased risk of hip fracture among patients with peripheral arterial disease (PAD), however, the results have been inconsistent. This meta-analysis was conducted with the aim to summarize all available evidence to better characterize the risk of incident hip fracture among these patients. A comprehensive literature review was conducted using the MEDLINE and EMBASE databases through October 2017 to identify all cohort and case-control studies that compared the risk of subsequent hip fracture between patients with PAD and individuals without PAD. Effect estimates of the included studies were extracted and combined using the random-effect, generic inverse variance method of DerSimonian and Laird. The systematic review process yielded six eligible cohort studies comprising 15,895 patients with PAD. There was a significant association between incident hip fracture and PAD with the pooled relative risk (RR) of 1.64 (95% CI, 1.17-2.29; I2, 80%), comparing patients with PAD and individuals without PAD. Subgroup analysis by study design revealed significant results for both prospective studies (pooled RR 1.60; 95% CI, 1.12-2.28; I2, 0%) and retrospective studies (pooled RR 1.72; 95% CI, 1.07-2.77; I2, 92%). The funnel plot is relatively asymmetric suggesting publication bias. This study found a significant association between PAD and hip fracture with the pooled RR of 1.64 (95% CI, 1.17-2.29) on comparing patients with PAD and individuals without PAD. Major limitations include high between-study heterogeneity, possibility of publication bias, and lack of data on the characteristics and type of hip fracture which may limit the clinical significance of the observations.


Modelling the effects of salt solutions on the hydration of calcium ions.
Classical molecular dynamics simulations of several aqueous alkali halide salt solutions have been used to determine the effect of electrolytes on the structure of water and the hydration properties of calcium ions. Compared with the simulations of Ca(2+) ions in pure liquid water, the frequency of water exchange in the first hydration shell of calcium, which is a fundamental process in controlling the reactivity of calcium(ii) aqua-ions, is drastically reduced in the presence of other electrolytes in solution. The strong stabilization of the hydration shell of Ca(2+) occurs not only when the halide anions are directly coordinated to calcium, but also when the alkali and halide ions are placed at or outside the second coordination shell of Ca(2+), suggesting that the reactivity of the first solvation shell of the calcium ion can be influenced by the specific affinity of other ions in solution for the water molecules coordinated to Ca(2+). Analysis of the hydrogen-bonded structure of water in the vicinity of the calcium ion shows that the average number of hydrogen bonds per water molecules, which is 1.8 in pure liquid water, decreases as the concentration of alkali-halide salts in solution increases, and that the temporal fluctuations of hydrogen bonds are significantly larger than those obtained for Ca(2+) in pure liquid water. This effect has been explained in terms of the dynamics of reorganization of the O-H···X(-) (X = F, Cl and Br) hydrogen bond. This work shows the importance of solution composition in determining the hydrogen-bonding network and ligand-exchange dynamics around metal ions, both in solution and at the mineral-water interfaces, which in turn has implications for interactions occurring at the mineral-water interface, ultimately controlling the mobilization of ions in the environment as well as in industrial processes.


Association of expired nitric oxide with occupational particulate exposure.
Particulate air pollution has been associated with adverse respiratory health effects. This study assessed the utility of expired nitric oxide to detect acute airway responses to metal-containing fine particulates. Using a repeated-measures study design, we investigated the association between the fractional concentration of expired nitric oxide (F(E)NO) and exposure to particulate matter with an aerodynamic mass median diameter of less than or equal to 2.5 micro m (PM(2.5)) in boilermakers exposed to residual oil fly ash and metal fumes. Subjects were monitored for 5 days during boiler repair overhauls in 1999 (n = 20) or 2000 (n = 14). The Wilcoxon median baseline F(E)NO was 10.6 ppb [95% confidence interval (CI): 9.1, 12.7] in 1999 and 7.4 ppb (95% CI: 6.7, 8.0) in 2000. The Wilcoxon median PM(2.5) 8-hr time-weighted average was 0.56 mg/m(3) (95% CI: 0.37, 0.93) in 1999 and 0.86 mg/m(3) (95% CI: 0.65, 1.07) in 2000. F(E)NO levels during the work week were significantly lower than baseline F(E)NO in 1999 (p < 0.001). A significant inverse exposure-response relationship between log-transformed F(E)NO and the previous workday's PM(2.5) concentration was found in 1999, after adjusting for smoking status, age, and sampling year. With each 1 mg/m(3) incremental increase in PM(2.5) exposure, log F(E)NO decreased by 0.24 (95% CI: -0.38, -0.10) in 1999. The lack of an exposure-response relationship between PM(2.5) exposure and F(E)NO in 2000 could be attributable to exposure misclassification resulting from the use of respirators. In conclusion, occupational exposure to metal-containing fine particulates was associated with significant decreases in F(E)NO in a survey of workers with limited respirator usage.